Mouse spleen cells sensitized in vitro to TNP-modified syngeneic spleen cells were tested for the generation of antibody-forming cells (as well as for cytotoxic function) by assaying the cultured lymphocytes in a plaque-forming cell (PFC) assay using TNA-modified sheep erythrocytes (TNP-SRC) as targets. A PFC response specific for the TNP-haptenic moiety was detected when the cultured spleen cells were from C57BL/10, B10.D2, or B10.A(5R) donors, whereas no response was detected in cultured lymphocytes from B10.A or B10.A(4R) donors. In contrast, spleen cells from all of the above mouse strains generated strong cytotoxic responses against TNP-modified self cells. These results indicate that the antibody response against the TNP hapten coupled to syngeneic cells is controlled by genetic factors mapping within the H-2 complex (possibly immune response genes) which do not affect T-cell-mediated cytotoxicity against TNP-self structures, and suggest that these antibodies and T-cell receptors recognize different antigenic specificities.